Pain is the most common symptomatic manifestation in humans. It is a complex condition, often of undefined aetiology. While acute pain is often the result of traumatism, visceral dyskinesia, acute inflammatory processes and infections, chronic pains are normally related to musculoskeletal, neuropathic and oncolytic affections and chronic inflammatory processes.
Several mechanisms are related to the occurrence of acute pains: traumatism of the musculoskeletal structures and soft tissues, dysfunctional anomalies, acute inflammatory processes, abdominal, thoracic or oropharyngeal visceral infections and dyskinesias may all trigger physical, mechanical, thermal and/or chemical stimuli that activate the nociceptors in the fibres of the peripheral nervous system. These transmit nociceptive information to the spinal medulla and subsequently to the hypothalamus and cortical areas involved in the processing of sensibility and originating in pain.
The more common chronic manifestations of pain are linked to chronic inflammatory processes normally seen in osteoarthritis, tendonitis, bursitis, spondylitis and other generally autoimmune degenerative processes. More than the actual pain, this process focuses the phenomenon of mechanical and thermal hyperalgesia related to decreased nociceptor thresholds which produce hypersensitivity to movement, mechanical deformation and heat. Hyperalgesia is caused by the action of numerous inflammatory mediators released in the painful regions, and more specifically bradykinin, acetylcholine, histamine and the cytokines, such as interleukins and tumour necrosis factors. The resulting hypersensitivity justifies the fact that inflamed tissues are pain free when at rest but become painful when stimulated.
The treatment and adequate control of pain and frequent inflammation is by pharmacotherapy, whereby several pharmacologic classes known in the state of the art are used for analgesic and anti-inflammatory purposes, with a large majority of these being obtained by means of chemical synthesis.
The most currently used analgesic and anti-inflammatory drugs are from the class of non-steroidal anti-inflammatory drugs (NSAID), such as salyclates, acetic acid derivatives, indolic derivatives and enol acid derivatives, amongst others.
However, the main problem related to the use of the anti-inflammatories specified above is due to their collateral effects, especially during prolonged administration. These effects include gastritis, ulceration, dyspepsia, nausea, vomiting, allergies, renal insufficiency, irreversible nephropathy, Reye's Syndrome, metabolic acidosis, hypertension and a risk of cardiovascular diseases.
In the case of non-selective NSAIDs, the non-specific inhibitors of the cyclooxygenase (COX) enzyme inhibit both COX-1, considered constitutive and responsible for the homeostasis of organs such as the stomach and kidneys, as well as COX-2, considered inductive and increasing in the organism at the genesis of the inflammatory process. COX-2 is responsible for the production of pro-inflammatory prostanoid mediators such as certain prostaglandin and leukotrienes. The inhibition of this enzyme (COX-2) is important for the reduction of the inflammatory process. However, the inhibition of COX-1 triggers the adverse effects described above and, more specifically, the gastrointestinal disorders because it is an important regulator of hydrochloric acid production as well as the production of the bicarbonate and mucous coating protecting the stomach from the acids and enzymes in the gastric juice.
The use of NSAIDs has been associated with serious complications. Such problems either impede adhering to the pharmacologic treatment per se, or render the treatment of chronic painful and/or inflammatory processes impossible.
In view of these limitations, it is understandable that the development of safer therapies or, in other words, with a better risk-benefit ratio, for the treatment of pain and inflammation is necessary, especially considering the risks associated to the pharmaceuticals currently in use.
In this context, phytotherapy presents itself as an appropriate alternative to the predominantly synthetic therapeutic arsenal.
The importance and chemical potentiality of medicinal plants can be ascertained from scientific research data results whereby approximately 50% of the medicines used clinically worldwide originate from natural products and derivatives (Gurib-Fakim, A., 2006, Mol. aspects med., 27, 1-93).
Frequently, the pharmacologic effects of phytotherapeutic medicines does not occur through the action of a single compound but rather through the combined activity of the various active substances contained or associated to it. Generally, the active substance isolated presents a different activity or lesser potency than that presented by the phytocomplex.
Contrary to medicines of synthetic origin, the active substances of phytotherapeutic medicines are almost always found in low concentrations which, generally, result in a lower incidence of adverse effects.
Despite the limitations encountered when obtaining, purifying and identifying natural products, recent technological advances have enabled obtaining more powerful and enhanced products when compared to synthetic products. (Koehn, F. E. & Carter, G. T., 2005, Nature, 4, 206-220).
A common issue to the use and production of phytomedicines relate to the variations in the concentration(s) of the active ingredient(s) which are generally secondary metabolites. These metabolites represent an interface between the plants and their environment and their synthesis is frequently affected by ambient conditions (such as seasonality, circadian rhythm, plant development stage, plant age, temperature, availability of water, ultraviolet (UV) radiation, soil nutrients, altitude, atmospheric composition and plant tissue damage). Such factors, as well as others such as gathering conditions, stabilisation, storage and industrial processing may all have an effect on the content of the secondary metabolites of medicinal plants and thus may also have a major influence on the quality of the phytotherapeutics being prepared. Therefore, apart from quality control involving modern analytic techniques and the standardisation of the intermediary products, the source and quality of the raw materials have a preponderant role for obtaining products of constantly reliable composition and reproducible therapeutic properties (Gobbo-Neto, L. & Lopes, N. P., 2007, Quím. Nova, 30, 374-381).
The Euphorbiaceae family originated from tropical Asia and the Pacific islands that consist of herbaceous plants, shrubs or trees generally producing ligneous latex. In Brazil, they are found in tropical areas being widely cultivated in coastal regions but may also be found in temperate regions. This family includes approximately 7.000 species with 317 genus (Webster, G. L., 1994, Annals of the Missouri. Botan. Garden, 81, 1, 3-32). Former studies of this family revealed a predominant presence of lipids, terpenoids, alkaloids and hydrocarbons (Hui, W. H. & Hoi, C. T., 1968, Aust. J. Chem., 21, 1675-7). Other studies also showed the importance of this family as food and in medicines as well as in industry (Gneco, S. et al., 1996, Bol. Soc. Chil. Quim., 41, 229-233; Villalobos, M. J. P. & astellanos, E. C., 1992, Grasas Y aceites, 43, 1, 39-44).
Among the several genus of the Euphorbiaceae family, the following should be mentioned being of the most importance due to their diversity, applications and commercial interest: Euphorbia, Croton, Phyllanthus, Jatropha, Sapium, Ricinus, Aleurites (Webster, G. L., 1994, Annals of the Missouri. Botan. Garden, 81, 1, 3-32). The genus Aleurites is subdivided in A. trisperma, A. cordata, A. montana, A. fordii, A. montance, A. rockinghamensis, apart form A. moluccana (Villalobos, M. J. P. & Castellanos, E. C., 1992, Grasas y aceites, 43, 1, 39-44; Misra, D. R. e Khastgir, H. N., 1970, Tetrahedron, 26, 12, 3017-3021; Cruz, G. L. Dicionário das plantas úteis do Brasil. 4th ed. Rio de Janeiro: Bertrand, 1964; Pio Correia, M. Dicionário das plantas úteis do Brasil e das exóticas cultivadas. IBDF, Brasília—DF (1984)V:294-295; Fozdar, B. I. et al., 1989, Phytochem., 28, 9, 2459-2461; Agarwal, R. et al., 1995, Fett. Wissench. Technologie-Fat Science Technol., 97, 526-527; Forster, P. I., 1996, Muelleria, 9, 5-13).
The Aleurites moluccana L. Willd., having the synonyms Aleurites triloba J. R. & G. Forst, Croton moluccanus L., Jatropha moluccana is an exotic tree native of Indonesia having been broadly introduced to Brazil and spreading from the state of Sao Paulo through to the state of Rio Grande do Sul, being especially abundant in the state of Santa Catarina. It is popularly known locally as “Nogueira-de-Iguape”, “Noz-da-Índia”, “Nogueira-da-Índia” “Nogueira-de-Bancul”, or simply “Nogueira” (Duke, J. A., Handbook of medicinal herbs. U.S.A.: CRC Press, 1991).
The use of Aleurites moluccana in traditional popular remedies is vast as is the case of most medicinal plants. It is used to control and as an empirical treatment for the following diseases or symptoms: fever, inflammations, asthma, conjunctivitis, hepatitis, headaches, ulcerations, diarrhoea, gonorrhoea and is also used against tumours, as a laxative stimulant, diaphoretic and anti-rheumatic. (Pio Correia, M. Dicionário das plantas úteis do Brasil e das exóticas cultivadas. IBDF, Brasília—DF, 1984, 294-295; Villalobos, M. J. P. & Castellanos, E. C., 1992, Grasas Y aceites, 43, 1, 39-44; Forster, P. I., 1996, Muelleria, 9, 5-13; Duke, James A. Handbook of medicinal herbs. U.S.A.: CRC Press, 1991; Stuppy, W. et al., 1999, Blumea, 44, 1, 73-98; Locher, C. P. et al., 1995, J. Ethnopharmacol., 49, 23; Hope, B. E. et al., 1993, Hawaii Med., 56, 6, 160-166). Nevertheless, very few studies able to systematically justify this broad therapeutic potential are described in the literature.
Certain prior studies by a Belgian research group demonstrated that the extracts of a plant collected in Hawaii showed antiviral activity, more specifically against the HIV virus (Locher, C. P. et al., 1996, Phytomedicine, 2, 259), as well as an antibacterial effect against Staphylococus aureus and Pseudomonas aeruginosa (Locher, C. P. et al., 1995, J. Ethnopharmacol., 49, 23).
Other preliminary studies conducted by the present inventors and their collaborators further demonstrated that non-standard hydroalcoholic extracts of Aleurites moluccana as well as their hexanic fractions, presented analgesic potential in an acetic acid-induced pain model in mice. Furthermore, analysis of the active ingredients isolated led to the identification of n-hentriacontane, alpha-amyrin, beta-amyrin, alpha-amirinone, beta-amirinone, stigmasterol, beta-sitosterol, campesterol, acetil aleuritolic acid (AAA), swertisin and 2″-O-rhamnosylswertisin, with some of these substances having significantly inhibited the acetic acid induced abdominal contortions in mice (Meyre-Silva, C. et al., 1998, Phytomedic., 5, 2, 109-113; Meyre-Silva, C. et al., 1999, Planta Med., 65, 3, 293-294).
In 1999, the inventors and their collaborators also demonstrated that swertisin, a flavonoid isolated from the leaves of Aleurites moluccana, did not have an analgesic effect with the acetic acid induced abdominal contortion model in mice. However, its derivate 2″-O-rhamnosylswertisin presented analgesia approximately 16 times more powerful than aspirin with this model, thus suggesting that the ramnosil group has an important role in the analgesic action of these compounds (Meyre-Silva, C. et al., 1999, Planta Med., 65, 3, 293-294).
Thus, former studies conducted by the inventors and their collaborators successfully identified potential use for the species in the development of new phytotherapeutic medicines.
The studies and research hereby presented by the inventors demonstrate new antinociceptive, anti-inflammatory and antipyretic activities related to the extracts of A. moluccana which are confirmed in the data and tests described below in the present report.
The inventors further identified a set of remarkable procedures, practices and conditions when compared to the current state of the art, as described below, that contribute to the use of Aleurites moluccana as a medicine/pharmaceutical input by guaranteeing that the specifications, safety and efficacy of its analgesic and anti-inflammatory properties remain reproducible and consistent.
In the light of the above, a process for obtaining a standardized extract from Aleurites moluccana, a process for isolating its marker and a process for preparing a phytotherapeutic pharmaceutical composition having analgesic, anti-inflammatory and antipyretic properties as well as a treatment method and its use as an alternative therapy to NSAIDs in view of its therapeutic potential and, possibly, better safety and tolerability characteristics are all obviously particularly interesting.